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Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance. Synopsis: Mutations in the ubiquitin-activating enzyme UBA1 cause autoinflammation (VEXAS syndrome), lung cancer in never-smokers (LCINS), and spinal muscular atrophy (SMA). Here, systematic mutation profiling defines mechanisms of UBA1 inactivation that are shared and distinct in these diseases. Identification of non-canonical VEXAS-causing UBA1 mutations that lead to aberrant ubiquitin adenylation, thiolation, and intramolecular oxyester formation. Non-canonical VEXAS mutations most prominently affect ubiquitin transfer to E2s. Two classes of UBA1 disease mutations either create a bottleneck at the E2 transfer step and are deficient in E2 charging and polyubiquitylation in cells, or render UBA1 activity thermolabile and exhibit subtle cellular defects. While non-canonical VEXAS mutations only fall in class 1 and SMA-associated mutations in class 2, LCNIS-associated mutations comprise class 1 and 2. Different classes of mutations in the ubiquitin-activating enzyme cause either autoinflammatory VEXAS syndrome, spinal muscular atrophy SMA, or lung cancer in never-smokers (LCINS). [ABSTRACT FROM AUTHOR]

Objective: To identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome) from a single‐center cohort of Italian patients with vasculitis, using a clinically oriented phenotype‐first approach. Methods: We retrospectively reviewed the clinical records of 147 consecutive male patients followed up in our vasculitis clinic from 2013 to date. All patients with a diagnosis of vasculitis and treatment‐resistant manifestations of inflammation, persistently elevated inflammation markers, and hematologic abnormalities were identified. Bone marrow aspirates were examined for the presence of vacuoles. Sequencing of ubiquitin‐activating enzyme E1 (UBA‐1) was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Results: Seven patients with vasculitis and concomitant features of VEXAS syndrome were identified. A final diagnosis of VEXAS syndrome was made in 3 of the 5 patients who underwent sequencing of UBA‐1 (diagnosis was made postmortem for 1 patient). In all 3 patients, examination of the bone marrow aspirate revealed vacuoles characteristic of VEXAS syndrome, and all 3 patients met the definitive World Health Organization criteria for myelodysplastic syndrome. Cytogenetic analysis showed normal karyotypes in all 3 patients. Conclusion: To our knowledge, this is the first report of VEXAS syndrome associated with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Our data emphasize the need to consider VEXAS syndrome when evaluating patients with various forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA‐associated vasculitis reported herein warrants further investigation. [ABSTRACT FROM AUTHOR]

Vaccination generates a neutralizing immune response against SARS-CoV-2. The genomic surveillance is showing the emergence of variants with mutations in spike, the main target of neutralizing antibodies. To understand the impact of these variants, we report the neutralization potency against alpha, gamma, and D614G SARSCoV- 2 variants in 44 individuals that received two doses of CoronaVac vaccine, an inactivated SARS-CoV-2 vaccine. Plasma samples collected at 60 days after the second dose of CoronaVac were analyzed by the reduction of cytopathic effect in Vero E6 cells with the three infectious variants of SARS-CoV-2. Plasma showed lower neutralization with alpha (geometric mean titer [GMT] = 18.5) and gamma (GMT = 10.0) variants than with D614G (GMT = 75.1) variant. Efficient neutralization against the alpha and gamma variants was not detected in 31.8% and 59.1% of plasma, respectively. These findings suggest the alpha and gamma variants could escape from neutralization by antibodies elicited by vaccination. Robust genomic and biological surveillance of viral variants could help to develop effective strategies for the control of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is the etiological agent of cervical cancer. Also, HPV has been associated with anogenital cancer, oropharyngeal cancer, genital warts, and other dermatological diseases. HPV infects epithelial cells and their replication is closely linked to epithelial differentiation. The presence of HPV DNA in peripheral blood mononuclear cells (PBMC) has been reported in some patients with head and neck cancer, cervical cancer, and other genital diseases. However, the presence of HPV DNA in blood in asymptomatic subjects is still unresolved. The objective of this study was to evaluate the presence of HPV DNA in PBMC from asymptomatic blood donors. Blood samples were collected from 207 healthy Chilean blood donors. Genomic DNA was extracted from PBMC and HPV DNA detection was performed by real‐time quantitative polymerase chain reaction assays with GP5+/6+ primers. HPV typing was carried out by genetic sequencing of a 140 to 150 bp fragment of the L1 gene. HPV DNA was detected in 6.8% (14/207) of blood donors. Single HPV infections were detected in seven blood donors. High‐risk HPV was found in 6.3% (13/207) of cases: nine blood donors were infected with HPV‐16, five with HPV‐18, two with HPV‐51, and one case was infected with either 32, 33, 45, 59, 66, 70, or 82. The median viral load value was 21.3 copies/mL blood or 13.4 HPV (+) cells per 10 4 PBMC. These results show that HPV DNA is present in PBMC from healthy blood donors and it suggests that blood could be a new route of HPV dissemination. Highlight: PBMC from 207 healthy Chilean blood donors were analyzed. HPV DNA and high‐risk HPV were detected in 6.8% (14) and 6.3% (13) of blood donors, respectively. Results show that HPV DNA is present in PBMC from blood donors and they suggest blood could be a new route of HPV dissemination. [ABSTRACT FROM AUTHOR]

Here, we evaluated the prevalence of Human Papillomavirus (HPV) in two groups of Chilean women. The first group consisted of 3235 women aged 18-64 years attended in six primary care centers of Santiago. The second group consisted of 456 women 18-85 aged who consulted the Gynaecology Department of the Reference Hospital of Santiago. Samples were collected from October 2012 to February 2016. Cervical swabs were analyzed both HPV genotyping by PCR and Reverse Line Blot, and cervical cytology by Pap testing. Results showed a prevalence of 12.0% HPV positive, 10.3% high-risk (HR) HPV types positive, 3.9% low-risk (LR) HPV types positive, and 1.0% Pap positive in group 1. The most frequent types were 16, 66, and 59, with a prevalence of 3.0%, 1.6%, and 1.5%, respectively. The prevalence were 71.9% HPV positive, 67.3% HR-HPV types positive, 13.6% LR-HPV types positive, and 62.5% Pap positive in group 2. The most frequent types were 16, 31, and 58, with prevalence of 33.6%, 10.5%, and 7.0%, respectively. Among infected women with HPV: 7.6% were infected with HPV16 or HPV18, 3.0% with HPV31, HPV33 or HPV45, and 6.7% with any other HR-HPV. These findings show great difference in HPV prevalence and types between primary care and reference center, and provide useful epidemiological information to assess the impact of HPV vaccination in the future. [ABSTRACT FROM AUTHOR]

Infection with human T-lymphotropic virus type 1/2 (HTLV-1/2) is a major health problem. HTLV-1/2 infection is endemic in Chile but representative donor prevalence data are lacking. Data on all blood donors in a large network of Chilean blood centers were examined during 2011-2013. Screening of HTLV-1/2 antibodies were measured by enzyme immunoassay (EIA) at all blood banks. Blood samples with anticoagulants from initially reactive blood donors were analyzed by serological confirmation tests (immunofluorescence or recombinant immunoblot) at the HTLV National Reference Laboratory of the Public Health Institute of Chile. Additionally, detection of HTLV-1 and HTLV-2 provirus in peripheral blood mononuclear cells (PBMCs) was performed in all blood donors as confirmatory test. Prevalence rates were calculated. Among 694,016 donors, 706 were seropositive for HTLV-1 (prevalence, 1.02 cases per 1,000; 95% confidence interval [CI], 0.94-1.09), and 97 were seropositive for HTLV-2 (prevalence, 0.14 cases per 1,000; 95%CI, 0.11-0.17). Prevalence of HTLV-1 differed considerably by region, from 0.51 to 1.69 per 1,000. Prevalence of HTLV-2 was similar across the country (0.12-0.16). HTLV-1 prevalence was associated with female sex, older age, and residence in the north of Chile. HTVL-2 prevalence was associated with older age. The HTLV-1 prevalence among Chilean blood donors was relatively high and could be reduced by improving donor recruitment and selection in high prevalence areas. Blood center data may contribute to surveillance for HTLV-1 and HTLV-2 infections. J. Med. Virol. 88:1067-1075, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives Pre-diabetes is an important indicator of future diabetes burden and many countries are reporting prevalence estimates of pre-diabetes. To date in Ireland, estimates of the prevalence of pre-diabetes were unavailable. Our objectives were to estimate the prevalence of pre-diabetes in a nationally representative sample of Irish adults and to explore determinants of pre-diabetes. Methods The Survey of Lifestyle Attitudes and Nutrition 2007 was a cross-sectional survey on health and lifestyle in a nationally representative sample of Irish adults. Analysis was performed on a subsample of 1132 participants ≥ 45 years who provided blood samples. Determination of pre-diabetes was based on American Diabetes Association HbA1c cut points of 39-46 mmol/mol (5.7-6.4%). To explore determinants, we modelled pre-diabetes prevalence as a function of a set of health system and socio-demographic variables using logistic regression. Results The overall weighted prevalence estimate of pre-diabetes in participants ≥ 45 years was 19.8% (95% CI 16.4-23.9). There was no significant difference between age or gender-specific prevalence rates. Obesity was significantly associated with pre-diabetes on univariate and multivariate analysis. Population attributable fraction estimates for excess BMI, physical inactivity and poor diet as causes of pre-diabetes were 31.3% (95% CI -3.9 to 54.5), 10.0% (95% CI -2.7 to 21.3) and 6.1% (95% CI -4.9 to 15.9), respectively. Conclusions The high levels of pre-diabetes detected in this study are worrying. Population level interventions to address diet and lifestyle factors are needed urgently to prevent progression to diabetes in high-risk individuals. [ABSTRACT FROM AUTHOR]

The spectral properties of novel styryl dyes developed for the biomacromolecules (such as DNA) detection and imaging were investigated. The energy structures of dye molecules were examined. The spectral data prove that dyes aggregate and interact with DNA. The essential increase of the fluorescence intensity of dyes in the presence of DNA was observed. The photostability and phototoxic influence on the DNA of several styryl dyes were studied by analyzing absorption, fluorescence, and phosphorescence spectra of these dyes and dye-DNA systems. Changes of the optical density value of dye-DNA solutions caused by the irradiation were fixed in the DNA and dye absorption wavelength regions. Fluorescence emission of dye-DNA complexes upon two-photon excitation at wavelength 1064nm with the 20-nanosecond pulsed YAG:Nd3+ laser and at 840nm with the 90 famtosecond pulsed Ti:sapphire laser was registered. The values of two-photon absorption cross-sections of dye-DNA complexes were evaluated. [ABSTRACT FROM AUTHOR]

This study examines the impact of travelling for treatment on cancer patients and their families. Twenty-eight consecutive cancer patients, who were receiving radiation therapy treatment and 19 family carers, completed a structured needs assessment questionnaire and an in-depth interview. Both patients and carers reported moderate to high levels of unmet psychological need. Carers were found to have higher levels of anxiety than patients, although both groups had higher anxiety levels than the general population. Taking more responsibility for household tasks and organising new living arrangements for the family were the most frequently identified demands of a dual burden of caring. Nearly 40% of carers reported some disruption to their schedule and half reported experiencing financial difficulties. The qualitative interviews highlight the disruption that parents and children experience under the present system, particularly in relation to the demands of family life and the need to maintain some level of continuity and security for children. [ABSTRACT FROM AUTHOR]

The article offers information on the disjoint families related to representing sets in mathematics. It presents information on the Generalized Continuum Hypothesis (G.C.H.) used in representing sets. It mentions that the cardinals are identified with the help of initial ordinals. It presents information on maximum cardinality of disjoint family related to, representing sets.

On peut augmenter le coefficient d'aplatissement (kurtosis) par un mouvement de la masse de probabilité, ne dépendant pas de la position et de l'échelle, des 'épaules' d'une distribution vers le centre et les ailes de celle-ci. On introduit une structure cohérente de relations d'ordre et de mesures, ne supposant pas la symétrie, qui représentent différentes formalisations de ce mouvement. à cette fin on définit des fonctions d'étendue et des graphiques étendue-étendue. Ces relations d'ordre imposent des formes de croissance sur les graphiques étendue-étendue des distributions impliquées. Les plus faibles de ces relations demandent une technique spécifique pour apparier l'échelle et la position des 'épaules'. Les mesures connues du coefficient d'aplatissement et les façons de les ordonner sont revues dans ce contexte général et des exemples sont présentés. [ABSTRACT FROM AUTHOR]

Injury control is one of the four priorities of the current National Health Strategy. Injury control targets are an integral part of this strategy and these require the measurement of the incidence of selected injuries. The strategy encourages local community based injury prevention programs. These programs need local data describing the determinants and distribution of injury in the particular community. Emergency department injury surveillance data is one source for this data. However manual data collection has been difficult to implement in Australian hospitals. This study reports an evaluation of the first electronic injury surveillance system integrated into an emergency department patient management system in Australia. This system was well accepted by emergency department staff and achieved good criteria validity in the range 88% to 100% on the injury data items. Emergency department nurses described the departmental requirement to collect injury data as being acceptable. Most nurses rated the injury coding system as satisfactory. [ABSTRACT FROM AUTHOR]

ABSTRACT Leucyl‐tRNA synthetase (LeuRS) is clinically validated molecular target for antibiotic development. Recently, we have reported several classes of small‐molecular inhibitors targeting aminoacyl‐adenylate binding site of Mycobacterium tuberculosis LeuRS with antibacterial activity. In this work, we performed in silico site‐directed mutagenesis of M. tuberculosis LeuRS synthetic site in order to identify the most critical amino acid residues for the interaction with substrate and prove binding modes of inhibitors. We carried out 20‐ns molecular dynamics (MD) simulations and used umbrella sampling (US) method for the calculation of the binding free energy (ΔGb) of leucyl‐adenylate with wild‐type and mutated forms of LeuRS. According to molecular modeling results, it was found that His89, Tyr93, and Glu660 are essential amino acid residues both for aminoacyl‐adenylate affinity and hydrogen bond formation. We have selected His89 for experimental site‐directed mutagenesis since according to our previous molecular docking results this amino acid residue was predicted to be important for inhibitor interaction in adenine‐binding region. We obtained recombinant mutant M. tuberculosis LeuRS H89A. Using aminoacylation assay we have found that the mutation of His89 to Ala in the active site of M. tuberculosis LeuRS results in significant decrease of inhibitory activity for compounds belonging to three different chemical classes—3‐phenyl‐5‐(1‐phenyl‐1H‐[1,2,3]triazol‐4‐yl)‐[1,2,4]oxadiazoles, N‐benzylidene‐N′‐thiazol‐2‐yl‐hydrazines, and 1‐oxo‐1H‐isothiochromene‐3‐carboxylic acid (4‐phenyl‐thiazol‐2‐yl)‐amide derivatives. Therefore, the interaction with His89 should be taken into account during further M. tuberculosis LeuRS inhibitors development and optimization. [ABSTRACT FROM AUTHOR]